The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation
Authors: Haowei Du, Angad Jolly, Christopher M. Grochowski, Bo Yuan, Moez Dawood, Shalini N. Jhangiani, He Li, Donna Muzny, Jawid M. Fatih, Zeynep Coban-Akdemir, Mary Esther Carlin, Angela E. Scheuerle, Karin Witzl, Jennifer E. Posey, Matthew Pendleton, Eoghan Harrington, Sissel Juul, P. J. Hastings, Weimin Bi, Richard A. Gibbs, Fritz J. Sedlazeck, James R. Lupski, Claudia M. B. Carvalho, Pengfei Liu
Journal: Genome Medicine (2022)

Abstract Background The multiple de novo copy number variant (M dn CNV) phenotype is described by having four or more constitutional de novo CNVs ( dn CNVs) arising independently throughout the human genome within one generation. It is a rare peri-zygotic mutational event, previously reported to be seen once in every 12,000 individuals referred for genome-wide chromosomal microarray analysis due to congenital abnormalities. These rare families provide a unique opportunity to understand the genetic factors of peri-zygotic genome instability and the impact of dn CNV on human diseases. Methods Chromosomal microarray analysis (CMA), array-based comparative genomic hybridization, short- and long-read genome sequencing (GS) were performed on the newly identified M dn CNV family to identify de novo mutations including dn CNVs, de novo single-nucleotide variants ( dn SNVs), and indels. Short-read GS was performed on four previously published M dn CNV families for dn SNV analysis. Trio-based rare variant analysis was performed on the newly identified individual and four previously published M dn CNV families to identify potential genetic etiologies contributing to the peri-zygotic genomic instability. Lin semantic similarity scores informed quantitative human phenotype ontology analysis on three M dn CNV families to identify gene(s) driving or contributing to the clinical phenotype. Results In the newly identified M dn CNV case, we revealed eight de novo tandem duplications, each ~ 1 Mb, with microhomology at 6/8 breakpoint junctions. Enrichment of de novo single-nucleotide variants (SNV; 6/79) and de novo indels (1/12) was found within 4 Mb of the dn CNV genomic regions. An elevated post-zygotic SNV mutation rate was observed in M dn CNV families. Maternal rare variant analyses identified three genes in distinct families that may contribute to the M dn CNV phenomenon. Phenotype analysis suggests that gene(s) within dn CNV regions contribute to the observed proband phenotype in 3/3 cases. CNVs in two cases, a contiguous gene duplication encompassing PMP22 and RAI1 and another duplication affecting NSD1 and SMARCC2 , contribute to the clinically observed phenotypic manifestations. Conclusions Characteristic features of dn CNVs reported here are consistent with a microhomology-mediated break-induced replication (MMBIR)-driven mechanism during the peri-zygotic period. Maternal genetic variants in DNA repair genes potentially contribute to peri-zygotic genomic instability. Variable phenotypic features were observed across a cohort of three M dn CNV probands, and computational quantitative phenotyping revealed that two out of three had evidence for the contribution of more than one genetic locus to the proband’s phenotype supporting the hypothesis of de novo multilocus pathogenic variation (MPV) in those families.